Dehydroepiandrosterone (DHEA) is an abundantly produced adrenal steroid. The serum concentration of its sulfate ester (DHEA-S) is approximately 20 times higher than that of any other circulating steroid hormone. Nestler et al., J. Clin. Endocrinol. Metab. 66:57 (1988). Peak serum DHEA and DHEA-S levels occur in a human at or about the age of 25 years and decrease rapidly thereafter to only about 10 percent of peak level by the age of 80-90 years. Despite the abundance and rapid turnover of this hormone, the physiological role of DHEA is still relatively unknown.
In the adrenal cortex, under stimulation of adrenocorticotrophic hormone (ACTH), cholesterol is degraded to pregnenolone, oxidized to progesterone, and further converted to cortisol. It is not known whether DHEA synthesis follows the same biosynthesis route as cortisol. Although DHEA is produced by the adrenal cortex, it is not found in the adrenal gland. The above-described biosynthetic route is duplicated in the testes and ovaries, except that the final products are testosterone and estradiol, respectively. Each gland secretes its own hormone while de-emphasizing the other product. While DHEA is not stored in the gonads, its secretion into blood plasma is similar to that for the DHEA of adrenal origin. The plasma level of DHEA is not significantly affected by castration; however, it is almost completely obliterated by adrenalectomy.
In young humans, the total rate of secretion of DHEA is about 5-10 mg per day. This secretion comes mostly from the adrenal cortex with a small amount coming from the testes or ovaries. After sexual maturity, the level of secretion of DHEA diminishes and almost ceases at senescence. This is not true for other hormones such as cortisol, ACTH or testosterone which remain fairly constant with age. While ovarian estrogen secretions cease in females at menopause, considerable amounts of estrogens can continue to be produced via the liver and intestinal conversion of DHEA to estradiol.
Recent studies in animals demonstrate that DHEA has beneficial effects in obesity and breast cancer. Schwartz Cancer Res. 39:1129 (1979); Schwartz Nutrition and Cancer, 3:46 (1981). DHEA also has been shown to have antihypercholesterolic effects in lowering lipid levels in rats. Ben-David et al., Proc. Soc. Exp. Biol. Med., 125:1136 (1967).
The importance of hypercholesterolemia, an elevated low-density lipoprotein (LDL) cholesterol level, as a major risk factor for the development of ischemic heart disease is widely accepted.
Barrett-Connors et al., New Engl. J. Med. 315:1519 (1986) showed that individuals with low circulating levels of DHEA-S die of heart disease at a higher rate than normal subjects. The oral administration of DHEA (1600 mg/day) reduces total serum cholesterol and LDL level by about 7.1 and 7.5 percent, respectively, in normal subjects. However, the administration of such relatively high doses of DHEA is undesirable.
The use of DHEA and other 17-keto steroids as medication for the prophylaxis and therapy of a retrovirus infection or for complications arising therefrom, e.g., acquired immune deficiency syndrome (AIDS) has been reported in SCRIP No. 1422, June 21, 1989, page 21 and in British Pat. Publication No. 2,204,237 by Colthurst, Ltd. Oral administration of relatively large doses of 1 to 2 grams per day has been tested in AIDS patients for improving their immune systems. In such tests, DHEA was administered orally alone or in combination with immunomodulators or antiviral agents.
Transdermal drug delivery devices for the continuous controlled transdermal administration of drugs are well known. Examples of such devices can be found in U.S. Pat. No. 3,731,683 to Zaffaroni, U.S. Pat. No. 3,797,494 to Zaffaroni, U.S. Pat. No. 4,031,894 to Uhrquhart et al., and U.S. Pat. No. 4,336,243 to Sanvordeker et al. Transdermal drug delivery devices are typically held in contact with the skin by means of a pressure-sensitive adhesive layer and are left in place for a period of 24 hours or longer.
Silicone pressure-sensitive adhesives are effective for holding such transdermal drug delivery systems to the skin for prolonged periods of time. Such silicone pressure-sensitive adhesives are known to be non-irritating and nonsensitizing to the skin, and have been used for the controlled release of nitroglycerin (Nitro-Disc.RTM., G.D. Searle Co., Skokie, Ill.). Other transdermal drug delivery systems have been developed for the delivery of various drugs. For example, the Transderm Scop.RTM. system for the delivery of scopolamine (CIBA-Geigy, Ardsley, N.Y.) utilizes a polyisobutylene pressure-sensitive adhesive layer.
It has now been found that therapeutically effective amounts of DHEA can be administered transdermally from a silicone based pressure-sensitive adhesive matrix which maintains its tack and adherence throughout the administration of DHEA.